The general objectives of the proposed research are to study the various factors which affect the action of anticoagulants such as dicumarol and warfarin. Various drugs and naturally occurring substances are known to affect the anticoagulants; among these are other drugs and long chain free fatty acids. Such agents will be studied in multiple combinations i.e., three or more in vitro and in vivo. The in vitro studies will be concerned with competition for binding sites in serum albumin. Such studies will be carried out using 14C dicumarol or warfarin and various other drugs using equilibrium dialysis procedures. The in vivo studies will be concerned with interactions affecting the excretion of radioactive anticoagulant or its metabolites in the bile of the rat. This procedure is a sensitive indicator of acute types of drug interactions. Among this are competition for binding sites on serum albumin and inhibition of drug metabolism or secretion in the bile. Chronic studies will also be carried out. Again, multiple combinations of drugs will be used. Pharmacokinetic analysis of multiple drug interactions will be carried out using a physiological-flow model. Appropriate computer programs will be developed to simulate the multiple interactions which will be studied in vivo.